ANNALS
Vol. 181
OF
~ ~ ~ ~ ~ ~ ~ ~ -WoO.-;
SURGE
JANUARY 1975
Sequential Changes in Cerebral Blood Flow and Distribution of Flow Within the Brain During Hemorrhagic Shock G. SLATER, M.D., B. C- VLADECK, M.D., R. BASSIN, M.D., R.S. BROWN, M.D., W.C. SHOEMAKER, M.D.
Sequential changes in cerebral blood flow as well as in regional
blood flow to the brain (brain stem, cerebellum, hypothalamus, white matter and grey matter) were measured in unanesthetized dogs subjected to gradual prolonged hemorrhage according to a protocol which stimulates the most commonly encountered type of clinical hemorrhagic shock. Microspheres labeled with five different radioactive isotopes were injected into a left atrial catheter at five different times: control, early hypotension (immediately after hemorrhage), late hypotension (just before reinfusion of the shed blood), as well as one and eight hours after reinfusion of the shed blood. Immediately after hemorrhage, the total cerebral blood flow decreased slightly, but increased-when calculated as a percent of the cardiac output. In the late hypotensive, hypovolemic stage, there was decreased flow calculated both as percentages of cardiac output and absolute flow as compared with the initial response to hemorrhage. Immediately after reinfusion of the shed blood, there were further reductions of flow. Eight hours subsequently, flow rose to values slightly above control. The patterns of each region was almost identical to that of the total cerebral flow. Since each of the major regions of the brain are approximately equally affected, changes in the level of consciousness and other cerebral functions occurring with hypovolemic shock may reflect circulation of the white matter as well as that of the whole brain. T E(CHNI(AL DIFFICULTIES in the measurement of
From the Department of Surgery, Mount Sinai School of Medicine of the City University of New York, New York, New York
structed after arterial injection of the radioactive gas. Analysis of tissue washout curves were used to calculate regional blood flow as well as white and grey matter blood flow. Other methods for measuring cerebral blood flow have incluided the measurement of the fraction uptake of 1311 labeled iodoantipyrine,15 the use of electromagnetic and tiltrasonic flow meters;22 and the use of heated thermocouples to measure blood flow by a thermal indicator dilution
techniquie.5 Ruidolf and Heyman18 introduced the use of radioactive
labeled microspheres to study the distribution of cardiac ouitput and regional blood flow. Several investigators have demonstrated the validity of this method for measuring blood flow.89 In the present study, we have used this method to estimate the cerebral circulation of the tinanesthetized dog. The sequential changes in the total blood flow, as well as regional flow to the brain during the course cerebral blood flow have made this organ one of the of graded hypotension and recovery were observed. most diffictult areas to study. The classical method for deterMaterials and Methods mining cerebral blood flow was developed by Kety and The experiments were performed on 14 mongrel dogs Schmidt10 who used a modification of the Fick principle 18-22 kg. A polyethylene catheter was placed in weighing indicator. Subseas the an inert gas, with nitrouis oxide, left atrium throtigh a small thoracotomy one week prior the inlabeled introduced isotopically quient investigations13'14 the Catheters were placed in the thoracic to blood experiment. cerebral to measure 85Kr and such as ert gases, 133Xe, flow. By placing several collimated gamma connecters out- aorta and right atrium tinder local anesthesia on the day of side the skull, simuiltaneous tissue washout curves were con- the experiment. The animal was then placed in a Pavlov stand and the experimental protocol was begun. Suibmitted for puiblication January 29, 1974. The catheters were attached to statham P23Dd pressure Reprint requests: William C. Shoemaker, M.D., Harbor General and the pressures were recorded on an Offner transducers Hospital, Department of Suirgery, U.C.L.A. School of Medicine, 1000 West Dynograph. The indicator dilation technique with inCarson Street, Torrance, California 90509.
SLATER AND OTHERS Aim. Stirg. * Januiary 1975 2 docyanin green was uised to measure cardiac outpuit. A white matter and grey matter. Each sample was weighed, Gilford photodensitometer was used to measure indocyanin placed in the lower third of a six-inch test tube and assayed green concentrations in the arterial blood. The Steward- on a Picker well-type scintillation spectrometer with dual Hamilton formula was uised to calculate the cardiac outplut channels. The counting was done at five different energy from the dye cturve.12 levels, previouisly determined for optimal separation of The protocol for inducing shock in the dogs has been variouis isotopes. Each radio assay was corrected for the reported in detail."1 A schematic representation of the radio-activity of the other isotopes using appropriate stanprotocol is shown in Fig. 1. After control measurements dards and a formuila similar to the one described by Rudolf blood was slowly removed over a three hour period until the and Heyman."8 mean arterial pressure reached 50 mm Hg. The pressure The CPM/Gram for the whole brain and for each inwas maintained at this level by removing or reinftusing small dividuial area were averaged and divided by the injected amouints of shed blood. The blood was kept in sterile plastic dose for each isotope. The results represented the percent of blood transfusion bags using heparin as the anticoagulant; the cardiac ouitpuit per gram of tissue. The percent cardiac the blood was rewarmed prior to infusion. After it was ouitpuit to the brain was obtained by multiplying the above necessary to return 20% of the shed blood to the dog to valuie by the total organ weight. The absolute flow was obmaintain its pressure at 50 mm Hg, the remainder of the tained by multiplying percent cardiac ouitput by the cardiac blood was infuised over one hour. Six dogs were sacrificed ouitpuit as measured by dye dilution. when they had survived 40 hours after transfusion; five dogs died duiring the hypotensive period. Results At five different times during the protocol radioactive The values for the sysetmic cardiac ouitpuit as well as the microspheres were injected through the left atrial catheter cerebral blood flow, expressed as a percent of cardiac ouput (Fig. 1). At the time of each injection, cardiac ouitput as well and as the absolute blood flow to the brain, at each of the as intravascular pressures were recorded. time stuidies are shown in Fig. 2. There was a marked periods The microspheres (3M Company) used were labeled with rise in the cerebral blood flow as a percent of cardiac outfive different isotopes: 'Ce, 76Sc, 85Sr, 51Cr and 1251. The put in the early hypotensive period, but a slight fall in the microspheres were 15 ± 5,u in diameter; specific activities late hypotension period; there was a large decrease one were abouit 10 mCi/g, except for 51Cr which was 52 mCi/g. hour after transfusion to near control values. The eight hour Approximately 0.025-0.05 mCi of each isotope was injected post-transfusion value was slightly above control. for each measurement. for the 3 the data suimmarizes distribuFigure regional After death or sacrifice of the animals auitopsies were per- tion of cardiac outpuit to the different areas of the formed and the brain was removed from the skull and studied. The general pattern of each region is almost brain weighed. By gross dissection samples were taken of the tical to that of the total brain. Each area differs only inidenabfollowing areas: brain stem, cerebellum, hypothalamus, soltute value of percent cardiac ouitpuit with the grey matter
CONTROL
HYPOTENSION
POST TRANSFUSION CONTROL
A
Os
I E
A
B
EARLY
B LATE
Di
D8
120
i001 s0
60
MEAN ARTERIAL PRESSURE
B
HYPOTENSION EARLY
POST TRANSFUSION
BLATE
DI
D8
4
L/MIN
DIAC OUTPUT
3CARDIAC OUTPUT
v
%CARDIAC OUTPUT TO BRAIN
Io_ 501
MLJ
4IUN
2 19 HOUKS 4 0 10 Fi;. 1. The protocol illuistrating mean arterial pressure and blood volume changes duiring the experiment. The labeled microspheres were injected at the time indicated by the arrows: control period (A), early hypotension (B early), late hypotension (B late), one houir post-transfusion (D,.), and eight houirs post transfusion (D8).
TBLOOD
FLOW TO BRAIN
28-J Fic. 2. The mean systemic cardiac output ( + one standard error of the mean); the percent of cardiac oUtpuit to the brain ( + 1 standard error of the mean); and the total blood flow to the brain ( + 1 standard error of the mean); at each stage of the experiment.
Vol. 181 * No. I CONTROL
A
CEREBRAL BLOOD FLOW IN SHOCK HYPOTENSION
B EARLY
BLATE
POST TRANSFUSION
D,
3
CONTROL HYPOTENSION POST TRANSFUSION
D8
A
B EARLY B lATE
DI
D8
90
2E-
801
50 1
CEREBELLUM
HYPOTHALAMUS MEDULLA
ARTERIAl PO2
70
GREY MATTER
WHITE MATTER
X-
O I
401
E
301
ARTERIAL
pCO 2
20
7460
Fic(. 3. The percent cardiac ouitpuit (per gram of tissue) to various parts of the brain at each stage of the experiment.
having the highest percentage and the medulla having the least of those areas examined. The ratio of grey matter to white matter in the control period was 1.84:1. The arterial blood gas data is presented in Figure 4. There was little change in the arterial oxygenation. The arterial pCO2 decreased during the hypotensive period and then returned towards normal after transfusion. Discussion The response of the cerebral circulation to hemorrhage hypotension has been reported by several investigators 3,20 as well as ourselves.19 There was a rise in the percent cardiac outpuit to the brain and only a modest reduction in the absolute blood flow. This pattern is thought to occur mainly as a passive phenomenon in which a larger proportion of the total blood flow goes to the brain because of the increased resistance to flow in those organs sensitive to alpha adrenergic activity; that is, the gastrointestinal tract, kidney, spleen and skin.' The circulation to the brain has been shown to respond poorly to catecholamines.4 The fall in arterial pCO2 that resulted from hyperventilation in the animals would be expected to produce cerebral vasoconstriction with decreased cerebral blood flow.'6 It is likely that the systemic acidosis, secondary to poor tissue perfusion, and the concomitant fall in extracellular cerebral pH was a significant factor in increasing cerebral blood flow.' Arterial oxygen tension did not change appreciably and probably was not an important factor in this study. The decrease in the percent of cardiac output to the brain between the early and late hypotensive stages, although still above control values may have been due to a decrease in the neurohuimoral responses in this period.2'2' The effect of an even lower arterial pCO2, with a rise in arterial pH, represents respiratory compensation for systemic as well as cerebral acidosis; this may have contributed to the fall in cerebral blood flow.
7 4201
ARTERIAL pH
7 380 7 340]
18 E
o o
E 14
.
ARTERIAL OXYGEN CONTENT
50
C
40 30 20 16C 1
E
140
120 ]cc
Fic. 4. Blood gas values. The mean ± 1 standard error of the mean for arterial P02, pCO2, pH, oxygen content.
After the return of blood volume to the animals, the percent of cardiac outpuit to the brain decreased to near control values. This reflects the redistribution of blood to areas of the body where resistance decreased in response to transftision. Since arterial pCO2 values increased only slightly after transfusion, this could not be the major regulatory mechanism operative at this stage. The basic patterns in the redistribution of cardiac output and regional blood flow in each anatomic area of the brain studied were approximately the same from period to period. Each area differed only in the absolute quantity of blood flow and not the percentage of cardiac output. This would imply.that the mechanisms regulating flow to the brain in
4
SLATER AND OTHERS
the dog are similar in each area. The ratio of grey matter flow to white matter flow remained relatively constant throughouit the study. The ratio of slightly less than 2: 1 is
9.
less than that reported both by Roth et al.17 using
microspheres and by those using the 85Kr clearance technique;7 however, this disparity may be due to differences in the techniques of anatomic dissection. The data are consistent with the view that circulatory changes to the major segments of the brain are relatively equially affected and that major redistributions of flow favoring the brain stem or other primitive areas do not occur tinder the conditions of these experiments. This suggests that the degree of cerebral impairment associated with the hypovolemic low cardiac outpuit state may reflect its circulatory status and that manifestations of cortical fuinction may be a usefuil index of the circulation of the whole brain. References 1. Betz, E.: Cerebral Blood Flow: Its Measurement and Regulations. Physiol. Rev., 52:595, 1972. 2. Coleman, B. and Glaviano V. U.: Tissue Levels of Norepinephrine and Epinephrine in Hemorrhagic Shock. Science, 139:54, 1962. 3. Fell, C.: Changes in Distribution of Blood Flow in Irreversible Hemorrhagic Shock. Am. J. Physiol., 210:863, 1966. 4. Goodman, L.S. and Gilman A.: Neurohuimeral Transmission and the Autonomic Nervouis System. In The Pharmacological Basis of Therapeutics. New York, Macmillan Co., 399-440, 1965. 5. Grangsjo, G., Sandblom, J., Ulfendahl, H. R. and Wolgast, M.: Theory of the Heated Thermocouple Principle. Acta. J. Physiol. Scand., 66:366, 1966. 6. Green, H. E., Rapela, C. E. and Conrad, C. E.: Resistance (Conductance) and Capacitance Phenomena in Terminal Vascular Beds. In Handbook of Physiology. Circulation. W. F. Hamilton and P. Dow editors, Washington, D. C. Am. J. Physiol. Soc. 1962, 2, Vol. II. 7. Haggendal, E. N., Wilson, J. and Norback, B.: Effect of Blood Corpuscle Concentration on Cerebral Blood Flow. Acta. Chir. Scand. Suippl., 354:13, 1966. 8. Hoffbrand, B. I. and Forsyth, R. P.: Validity Studies of the Radioactive
Microsphere Method for the Study of the Distribution of Cardiac
10. 11.
12. 13.
14. 15. 16.
17. 18. 19.
20.
21.
22.
Anni. Suirg. * Jantiary 1975
Otutput, Organ Blood Flow and Resistance in the Conscious Rhesus Monkey, Cardiovasc. Res., 3:426, 1969. Kaihara, S., Van Heerden, D. D., Migita, T. and Wagner Jr. H. N.: Measurement of Distribuition of Cardiac Outpuit. J. Appl. Physiol., 25:696, 1968. Kety, S. S. and Schmidt C. F.: The Determination of Cerebral Blood Flow in Man by the Use of Nitrous Oxide in Low Concentrations. Am. J. Physiol., 143:53, 1945. Kim, S. I., Desai, J. M. and Shoemaker, W. C.: Sequence of Cardiorespiratory Alterations After Gradual Prolonged Hemorrhage in Conscious Dogs. Am. J. Physiol., 216:1044, 1969. Kinsman, J. M., Moore Jr., J. W. and Hamilton, W. F.: Studies on the Circulation 1: Injection Methods Physical and Mathematical Considerations. Am. J. Physiol., 89:322, 1929. Lassen, N. A., Hoedt-Rasmussen, K., Sorensen, S. C., Skinhoj, E., Cronquist, E. S., Bodforss, B. and Ingvar, D. H.: Regional Cerebral Blood Flow in Man Determined by a Radioactive Inert Gas (Krypton 85). Neurol., 13:719, 1963. Mallet, B. L. and Veall, N.: The Measurement of Regional Cerebral Clearance Rates in Man Using Xenon 133 Inhalation and Extracranial Recording. Clin. Sci., 29:179, 1965. Reinmuth, 0. M. and Scheinberg, P.: A Method for Rapid Serial Labelled 4Cerebral Flow Determinations Using iodoantipyrine. Excerpta Med., 39:80, 1961. Reivich, M.: Arterial PaCO2 and Cerebral Hemodynamics Am. J. Physiol., 206:25, 1964. Roth, J. A., Greenfield, A. J., Kaihara, S. and Wagner. H. N.: Total and Regional Cerebral Blood Flow in Unanesthetized Dogs. Am. J. Physiol.. 219:96, 1970. Rudolph, A. M. and Heyman, M. A.: The Circulation of the Fetus In Utero: Methods for Studying Distribution of Blood Flow, Cardiac Outpuit and Organ Blood Flow. Circ. Res., 21:163, 1967. Slater, G. I., Bassin, R., Vladeck, B. C. and Shoemaker, W. C.: Sequential Changes in Distribution of Cardiac Output in Hemorrhagic shock. Surgery, 73:714, 1973. Stone, H. H., Donnelly, C. C., Mackrell, T. N., Braustater, B. J. and Nemir Jr. P.: The Effect of Acute Hemorrhagic Shock on Cerebral Circulation and Metabolism of Man. In Shock and Hypotension. New York, Grune and Stratton, 257-264, 1965. Walton, R. P., Richardson, J. A., Walton, Jr., R. P. and Thompson, W. L.: Sympathetic Influence During Hemorrhagic Hypotension. Am. J. Physiol., 197:223, 1959. Yoshida, K., Meyer J. S., Sakamoto, K. and Harda, J.: Autoreguilation of Cerebral Blood Flow. Circ. Res., 19:726, 1966.
Vol. 181
OF
~ ~ ~ ~ ~ ~ ~ ~ -WoO.-;
SURGE
JANUARY 1975
Sequential Changes in Cerebral Blood Flow and Distribution of Flow Within the Brain During Hemorrhagic Shock G. SLATER, M.D., B. C- VLADECK, M.D., R. BASSIN, M.D., R.S. BROWN, M.D., W.C. SHOEMAKER, M.D.
Sequential changes in cerebral blood flow as well as in regional
blood flow to the brain (brain stem, cerebellum, hypothalamus, white matter and grey matter) were measured in unanesthetized dogs subjected to gradual prolonged hemorrhage according to a protocol which stimulates the most commonly encountered type of clinical hemorrhagic shock. Microspheres labeled with five different radioactive isotopes were injected into a left atrial catheter at five different times: control, early hypotension (immediately after hemorrhage), late hypotension (just before reinfusion of the shed blood), as well as one and eight hours after reinfusion of the shed blood. Immediately after hemorrhage, the total cerebral blood flow decreased slightly, but increased-when calculated as a percent of the cardiac output. In the late hypotensive, hypovolemic stage, there was decreased flow calculated both as percentages of cardiac output and absolute flow as compared with the initial response to hemorrhage. Immediately after reinfusion of the shed blood, there were further reductions of flow. Eight hours subsequently, flow rose to values slightly above control. The patterns of each region was almost identical to that of the total cerebral flow. Since each of the major regions of the brain are approximately equally affected, changes in the level of consciousness and other cerebral functions occurring with hypovolemic shock may reflect circulation of the white matter as well as that of the whole brain. T E(CHNI(AL DIFFICULTIES in the measurement of
From the Department of Surgery, Mount Sinai School of Medicine of the City University of New York, New York, New York
structed after arterial injection of the radioactive gas. Analysis of tissue washout curves were used to calculate regional blood flow as well as white and grey matter blood flow. Other methods for measuring cerebral blood flow have incluided the measurement of the fraction uptake of 1311 labeled iodoantipyrine,15 the use of electromagnetic and tiltrasonic flow meters;22 and the use of heated thermocouples to measure blood flow by a thermal indicator dilution
techniquie.5 Ruidolf and Heyman18 introduced the use of radioactive
labeled microspheres to study the distribution of cardiac ouitput and regional blood flow. Several investigators have demonstrated the validity of this method for measuring blood flow.89 In the present study, we have used this method to estimate the cerebral circulation of the tinanesthetized dog. The sequential changes in the total blood flow, as well as regional flow to the brain during the course cerebral blood flow have made this organ one of the of graded hypotension and recovery were observed. most diffictult areas to study. The classical method for deterMaterials and Methods mining cerebral blood flow was developed by Kety and The experiments were performed on 14 mongrel dogs Schmidt10 who used a modification of the Fick principle 18-22 kg. A polyethylene catheter was placed in weighing indicator. Subseas the an inert gas, with nitrouis oxide, left atrium throtigh a small thoracotomy one week prior the inlabeled introduced isotopically quient investigations13'14 the Catheters were placed in the thoracic to blood experiment. cerebral to measure 85Kr and such as ert gases, 133Xe, flow. By placing several collimated gamma connecters out- aorta and right atrium tinder local anesthesia on the day of side the skull, simuiltaneous tissue washout curves were con- the experiment. The animal was then placed in a Pavlov stand and the experimental protocol was begun. Suibmitted for puiblication January 29, 1974. The catheters were attached to statham P23Dd pressure Reprint requests: William C. Shoemaker, M.D., Harbor General and the pressures were recorded on an Offner transducers Hospital, Department of Suirgery, U.C.L.A. School of Medicine, 1000 West Dynograph. The indicator dilation technique with inCarson Street, Torrance, California 90509.
SLATER AND OTHERS Aim. Stirg. * Januiary 1975 2 docyanin green was uised to measure cardiac outpuit. A white matter and grey matter. Each sample was weighed, Gilford photodensitometer was used to measure indocyanin placed in the lower third of a six-inch test tube and assayed green concentrations in the arterial blood. The Steward- on a Picker well-type scintillation spectrometer with dual Hamilton formula was uised to calculate the cardiac outplut channels. The counting was done at five different energy from the dye cturve.12 levels, previouisly determined for optimal separation of The protocol for inducing shock in the dogs has been variouis isotopes. Each radio assay was corrected for the reported in detail."1 A schematic representation of the radio-activity of the other isotopes using appropriate stanprotocol is shown in Fig. 1. After control measurements dards and a formuila similar to the one described by Rudolf blood was slowly removed over a three hour period until the and Heyman."8 mean arterial pressure reached 50 mm Hg. The pressure The CPM/Gram for the whole brain and for each inwas maintained at this level by removing or reinftusing small dividuial area were averaged and divided by the injected amouints of shed blood. The blood was kept in sterile plastic dose for each isotope. The results represented the percent of blood transfusion bags using heparin as the anticoagulant; the cardiac ouitpuit per gram of tissue. The percent cardiac the blood was rewarmed prior to infusion. After it was ouitpuit to the brain was obtained by multiplying the above necessary to return 20% of the shed blood to the dog to valuie by the total organ weight. The absolute flow was obmaintain its pressure at 50 mm Hg, the remainder of the tained by multiplying percent cardiac ouitput by the cardiac blood was infuised over one hour. Six dogs were sacrificed ouitpuit as measured by dye dilution. when they had survived 40 hours after transfusion; five dogs died duiring the hypotensive period. Results At five different times during the protocol radioactive The values for the sysetmic cardiac ouitpuit as well as the microspheres were injected through the left atrial catheter cerebral blood flow, expressed as a percent of cardiac ouput (Fig. 1). At the time of each injection, cardiac ouitput as well and as the absolute blood flow to the brain, at each of the as intravascular pressures were recorded. time stuidies are shown in Fig. 2. There was a marked periods The microspheres (3M Company) used were labeled with rise in the cerebral blood flow as a percent of cardiac outfive different isotopes: 'Ce, 76Sc, 85Sr, 51Cr and 1251. The put in the early hypotensive period, but a slight fall in the microspheres were 15 ± 5,u in diameter; specific activities late hypotension period; there was a large decrease one were abouit 10 mCi/g, except for 51Cr which was 52 mCi/g. hour after transfusion to near control values. The eight hour Approximately 0.025-0.05 mCi of each isotope was injected post-transfusion value was slightly above control. for each measurement. for the 3 the data suimmarizes distribuFigure regional After death or sacrifice of the animals auitopsies were per- tion of cardiac outpuit to the different areas of the formed and the brain was removed from the skull and studied. The general pattern of each region is almost brain weighed. By gross dissection samples were taken of the tical to that of the total brain. Each area differs only inidenabfollowing areas: brain stem, cerebellum, hypothalamus, soltute value of percent cardiac ouitpuit with the grey matter
CONTROL
HYPOTENSION
POST TRANSFUSION CONTROL
A
Os
I E
A
B
EARLY
B LATE
Di
D8
120
i001 s0
60
MEAN ARTERIAL PRESSURE
B
HYPOTENSION EARLY
POST TRANSFUSION
BLATE
DI
D8
4
L/MIN
DIAC OUTPUT
3CARDIAC OUTPUT
v
%CARDIAC OUTPUT TO BRAIN
Io_ 501
MLJ
4IUN
2 19 HOUKS 4 0 10 Fi;. 1. The protocol illuistrating mean arterial pressure and blood volume changes duiring the experiment. The labeled microspheres were injected at the time indicated by the arrows: control period (A), early hypotension (B early), late hypotension (B late), one houir post-transfusion (D,.), and eight houirs post transfusion (D8).
TBLOOD
FLOW TO BRAIN
28-J Fic. 2. The mean systemic cardiac output ( + one standard error of the mean); the percent of cardiac oUtpuit to the brain ( + 1 standard error of the mean); and the total blood flow to the brain ( + 1 standard error of the mean); at each stage of the experiment.
Vol. 181 * No. I CONTROL
A
CEREBRAL BLOOD FLOW IN SHOCK HYPOTENSION
B EARLY
BLATE
POST TRANSFUSION
D,
3
CONTROL HYPOTENSION POST TRANSFUSION
D8
A
B EARLY B lATE
DI
D8
90
2E-
801
50 1
CEREBELLUM
HYPOTHALAMUS MEDULLA
ARTERIAl PO2
70
GREY MATTER
WHITE MATTER
X-
O I
401
E
301
ARTERIAL
pCO 2
20
7460
Fic(. 3. The percent cardiac ouitpuit (per gram of tissue) to various parts of the brain at each stage of the experiment.
having the highest percentage and the medulla having the least of those areas examined. The ratio of grey matter to white matter in the control period was 1.84:1. The arterial blood gas data is presented in Figure 4. There was little change in the arterial oxygenation. The arterial pCO2 decreased during the hypotensive period and then returned towards normal after transfusion. Discussion The response of the cerebral circulation to hemorrhage hypotension has been reported by several investigators 3,20 as well as ourselves.19 There was a rise in the percent cardiac outpuit to the brain and only a modest reduction in the absolute blood flow. This pattern is thought to occur mainly as a passive phenomenon in which a larger proportion of the total blood flow goes to the brain because of the increased resistance to flow in those organs sensitive to alpha adrenergic activity; that is, the gastrointestinal tract, kidney, spleen and skin.' The circulation to the brain has been shown to respond poorly to catecholamines.4 The fall in arterial pCO2 that resulted from hyperventilation in the animals would be expected to produce cerebral vasoconstriction with decreased cerebral blood flow.'6 It is likely that the systemic acidosis, secondary to poor tissue perfusion, and the concomitant fall in extracellular cerebral pH was a significant factor in increasing cerebral blood flow.' Arterial oxygen tension did not change appreciably and probably was not an important factor in this study. The decrease in the percent of cardiac output to the brain between the early and late hypotensive stages, although still above control values may have been due to a decrease in the neurohuimoral responses in this period.2'2' The effect of an even lower arterial pCO2, with a rise in arterial pH, represents respiratory compensation for systemic as well as cerebral acidosis; this may have contributed to the fall in cerebral blood flow.
7 4201
ARTERIAL pH
7 380 7 340]
18 E
o o
E 14
.
ARTERIAL OXYGEN CONTENT
50
C
40 30 20 16C 1
E
140
120 ]cc
Fic. 4. Blood gas values. The mean ± 1 standard error of the mean for arterial P02, pCO2, pH, oxygen content.
After the return of blood volume to the animals, the percent of cardiac outpuit to the brain decreased to near control values. This reflects the redistribution of blood to areas of the body where resistance decreased in response to transftision. Since arterial pCO2 values increased only slightly after transfusion, this could not be the major regulatory mechanism operative at this stage. The basic patterns in the redistribution of cardiac output and regional blood flow in each anatomic area of the brain studied were approximately the same from period to period. Each area differed only in the absolute quantity of blood flow and not the percentage of cardiac output. This would imply.that the mechanisms regulating flow to the brain in
4
SLATER AND OTHERS
the dog are similar in each area. The ratio of grey matter flow to white matter flow remained relatively constant throughouit the study. The ratio of slightly less than 2: 1 is
9.
less than that reported both by Roth et al.17 using
microspheres and by those using the 85Kr clearance technique;7 however, this disparity may be due to differences in the techniques of anatomic dissection. The data are consistent with the view that circulatory changes to the major segments of the brain are relatively equially affected and that major redistributions of flow favoring the brain stem or other primitive areas do not occur tinder the conditions of these experiments. This suggests that the degree of cerebral impairment associated with the hypovolemic low cardiac outpuit state may reflect its circulatory status and that manifestations of cortical fuinction may be a usefuil index of the circulation of the whole brain. References 1. Betz, E.: Cerebral Blood Flow: Its Measurement and Regulations. Physiol. Rev., 52:595, 1972. 2. Coleman, B. and Glaviano V. U.: Tissue Levels of Norepinephrine and Epinephrine in Hemorrhagic Shock. Science, 139:54, 1962. 3. Fell, C.: Changes in Distribution of Blood Flow in Irreversible Hemorrhagic Shock. Am. J. Physiol., 210:863, 1966. 4. Goodman, L.S. and Gilman A.: Neurohuimeral Transmission and the Autonomic Nervouis System. In The Pharmacological Basis of Therapeutics. New York, Macmillan Co., 399-440, 1965. 5. Grangsjo, G., Sandblom, J., Ulfendahl, H. R. and Wolgast, M.: Theory of the Heated Thermocouple Principle. Acta. J. Physiol. Scand., 66:366, 1966. 6. Green, H. E., Rapela, C. E. and Conrad, C. E.: Resistance (Conductance) and Capacitance Phenomena in Terminal Vascular Beds. In Handbook of Physiology. Circulation. W. F. Hamilton and P. Dow editors, Washington, D. C. Am. J. Physiol. Soc. 1962, 2, Vol. II. 7. Haggendal, E. N., Wilson, J. and Norback, B.: Effect of Blood Corpuscle Concentration on Cerebral Blood Flow. Acta. Chir. Scand. Suippl., 354:13, 1966. 8. Hoffbrand, B. I. and Forsyth, R. P.: Validity Studies of the Radioactive
Microsphere Method for the Study of the Distribution of Cardiac
10. 11.
12. 13.
14. 15. 16.
17. 18. 19.
20.
21.
22.
Anni. Suirg. * Jantiary 1975
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